tbuckley/cabot-search huggingface dataset:
SAFFRON-103: a phase 1b study of the safety and efficacy of sitravatinib combined with tislelizumab in patients with locally advanced or metastatic non-small cell lung cancer
Authors: Jun Zhao, Xinmin Yu, Dingzhi Huang, Zhiyong Ma, Bo Gao, Jiuwei Cui, Qian Chu, Qing Zhou, Meili Sun, Daphne Day, Jingxun Wu, Hongming Pan, Lifeng Wang, Mark Voskoboynik, Zhehai Wang, Yunpeng Liu, Hui Li, Juan Zhang, Yanyan Peng, Yi-Long Wu
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Some patients with locally advanced/metastatic non-small cell lung cancer (NSCLC) respond poorly to anti-programmed cell death protein 1 (PD-1)/anti-programmed death-ligand 1 (PD-L1) treatments. Combination with other agents may improve the outcomes. This open-label, multicenter, phase 1b trial investigated the combination of sitravatinib, a spectrum-selective tyrosine kinase inhibitor, plus anti-PD-1 antibody tislelizumab. Methods Patients with locally advanced/metastatic NSCLC were enrolled (Cohorts A, B, F, H, and I; N=22–24 per cohort). Cohorts A and F included patients previously treated with systemic therapy, with anti-PD-(L)1-resistant/refractory non-squamous (cohort A) or squamous (cohort F) disease. Cohort B included patients previously treated with systemic therapy, with anti-PD-(L)1-naïve non-squamous disease. Cohorts H and I included patients without prior systemic therapy for metastatic disease, no prior anti-PD-(L)1/immunotherapy, with PD-L1-positive non-squamous (cohort H) or squamous (cohort I) histology. Patients received sitravatinib 120 mg orally one time per day plus tislelizumab 200 mg intravenously every 3 weeks, until study withdrawal, disease progression, unacceptable toxicity, or death. The primary endpoint was safety/tolerability among all treated patients (N=122). Secondary endpoints included investigator-assessed tumor responses and progression-free survival (PFS). Results Median follow-up was 10.9 months (range: 0.4–30.6). Treatment-related adverse events (TRAEs) occurred in 98.4% of the patients, with ≥Grade 3 TRAEs in 51.6%. TRAEs led to discontinuation of either drug in 23.0% of the patients. Overall response rate was 8.7% (n/N: 2/23; 95% CI: 1.1% to 28.0%), 18.2% (4/22; 95% CI: 5.2% to 40.3%), 23.8% (5/21; 95% CI: 8.2% to 47.2%), 57.1% (12/21; 95% CI: 34.0% to 78.2%), and 30.4% (7/23; 95% CI: 13.2% to 52.9%) in cohorts A, F, B, H, and I, respectively. Median duration of response was not reached in cohort A and ranged from 6.9 to 17.9 months across other cohorts. Disease control was achieved in 78.3–90.9% of the patients. Median PFS ranged from 4.2 (cohort A) to 11.1 months (cohort H). Conclusions In patients with locally advanced/metastatic NSCLC, sitravatinib plus tislelizumab was tolerable for most patients, with no new safety signals and overall safety profiles consistent with known profiles of these agents. Objective responses were observed in all cohorts, including in patients naïve to systemic and anti-PD-(L)1 treatments, or with anti-PD-(L)1 resistant/refractory disease. Results support further investigation in selected NSCLC populations. Trial registration number NCT03666143 .
Safety and efficacy of autologous and allogeneic humanized CD19-targeted CAR-T cell therapy for patients with relapsed/refractory B-ALL
Authors: Fengmei Song, Yongxian Hu, Yanlei Zhang, Mingming Zhang, Tingting Yang, Wenjun Wu, Simao Huang, Huijun Xu, Alex H Chang, He Huang, Guoqing Wei
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Murine chimeric antigen receptor T (CAR-T) cell therapy has demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). However, the potential immunogenicity of the murine single-chain variable fragment domain may limit the persistence of CAR-T cell, leading to relapse. Methods We performed a clinical trial to determine the safety and efficacy of autologous and allogeneic humanized CD19-targeted CAR-T cell (hCART19) for R/R B-ALL. Fifty-eight patients (aged 13–74 years) were enrolled and treated between February 2020 and March 2022. The endpoints were complete remission (CR) rate, overall survival (OS), event-free survival (EFS), and safety. Results Overall, 93.1% (54/58) of patients achieved CR or CR with incomplete count recovery (CRi) by day 28, with 53 patients having minimal residual disease negativity. With a median follow-up of 13.5 months, the estimated 1-year OS and EFS were 73.6% (95% CI 62.1% to 87.4%) and 46.0% (95% CI 33.7% to 62.8%), with a median OS and EFS of 21.5 months and 9.5 months, respectively. No significant increase in human antimouse antibodies was observed following infusion (p=0.78). Duration of B-cell aplasia in the blood was observed for as long as 616 days, which was longer than that in our prior mCART19 trial. All toxicities were reversible, including severe cytokine release syndrome, which developed in 36% (21/58) of patients and severe neurotoxicity, which developed in 5% (3/58) of patients. Compared with our prior mCART19 trial, patients treated with hCART19 had longer EFS without increased toxicity. Additionally, our data also suggest that patients treated with consolidation therapy, including allogeneic hematopoietic stem cell transplantation or CD22-targeted CAR-T cell, following hCART19 therapy had a longer EFS than those without consolidation therapy. Conclusion hCART19 has good short-term efficacy and manageable toxicity in R/R B-ALL patients. Trial registration number NCT04532268 .
Prevalence of Chronic Kidney Disease in China
Authors: Limin Wang, Xin Xu, Mei Zhang, Caihong Hu, Xiao Zhang, Chun Li, Sheng Nie, Zhengjing Huang, Zhenping Zhao, Fan Fan Hou, Maigeng Zhou
Journal: JAMA Internal Medicine (2023)

Importance To our knowledge, there has been no update on the prevalence of chronic kidney disease (CKD) in China since 2012. Objective To provide periodic nationwide data on the prevalence of CKD and the associated behavioral and metabolic risk factors in China. Design, Setting, and Participants This nationally representative cross-sectional study included data from 176 874 adults from all 31 provincial-level administrative divisions in mainland China, as reported in the sixth China Chronic Disease and Risk Factor Surveillance conducted from August 2018 to June 2019. Data analysis was performed in 2021 to 2022. Exposures Serum creatinine, urinal creatinine, and urine albumin were measured for all participants. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine using the CKD-EPI equation. Main Outcomes and Measures The primary outcome was weighted prevalence of CKD in the overall population and different strata, defined as presence of impaired kidney function (eGFR of &amp;amp;lt;60 mL/min/1.73m 2 ) or albuminuria (urine albumin-to-creatinine ratio of ≥30 mg/g). Secondary outcomes were awareness of CKD and control of comorbidities. Logistic regression was used to examine the association of sociodemographic characteristics, behavioral and dietary habits, physical activity, and comorbidities with CKD. Results A total of 184 876 participants contributed data to this study, and of the 176 874 adults 18 years and older with measurements of eGFR and urine albumin-to-creatinine ratio in 2018 to 2019, the mean age was 43.8 years and the weighted proportion of women was 44.6%. The estimated prevalence of CKD, impaired kidney function, and albuminuria were 8.2%, 2.2%, and 6.7%, respectively. A higher prevalence of CKD was observed in the subgroups characterized by older age, female gender, non-Han ethnicity, residency of rural or north and central parts of China, receiving less education or lower income, former smoking, no alcohol drinking, lacking physical activity, and presence of risk factors such as obesity, hypertension, diabetes, dyslipidemia, and self-reported cardiovascular disease. Among the adults with CKD, 73.3%, 25.0%, and 1.8% were at stage 1 to 2, 3, and 4 to 5, respectively, and the awareness of CKD was 10.0%. Conclusions and Relevance This cross-sectional study found a weighted estimated of 82 million adults with CKD in China in 2018 to 2019. The prevalence appears to have decreased by 30% in the past decade. Better environmental protection, integration of CKD into the national public health surveillance program, and control of common CKD comorbidities appear to be associated with reducing the disease burden of CKD.
Gestational palmitic acid suppresses embryonic GATA-binding protein 4 signaling and causes congenital heart disease
Authors: Rui Zhao, Li Cao, Wen-Jun Gu, Lei Li, Zhong-Zhong Chen, Jie Xiang, Ze-Yu Zhou, Bo Xu, Wei-Dong Zang, Xiang-Yu Zhou, Jing Cao, Kun Sun, Jian-Yuan Zhao
Journal: Cell Reports Medicine (2023)

Dysregulated maternal fatty acid metabolism increases the risk of congenital heart disease (CHD) in offspring with an unknown mechanism, and the effect of folic acid fortification in preventing CHD is controversial. Using gas chromatography coupled to either a flame ionization detector or mass spectrometer (GC-FID/MS) analysis, we find that the palmitic acid (PA) concentration increases significantly in serum samples of pregnant women bearing children with CHD. Feeding pregnant mice with PA increased CHD risk in offspring and cannot be rescued by folic acid supplementation. We further find that PA promotes methionyl-tRNA synthetase (MARS) expression and protein lysine homocysteinylation (K-Hcy) of GATA4 and results in GATA4 inhibition and abnormal heart development. Targeting K-Hcy modification by either genetic ablation of Mars or using N-acetyl-L-cysteine (NAC) decreases CHD onset in high-PA-diet-fed mice. In summary, our work links maternal malnutrition and MARS/K-Hcy with the onset of CHD and provides a potential strategy in preventing CHD by targeting K-Hcy other than folic acid supplementation.
TCR-engineered adoptive cell therapy effectively treats intracranial murine glioblastoma
Authors: Maximilian O Schaettler, Rupen Desai, Anthony Z Wang, Alexandra J Livingstone, Dale K Kobayashi, Andrew T Coxon, Jay A Bowman-Kirigin, Connor J Liu, Mao Li, Diane E Bender, Michael J White, David M Kranz, Tanner M Johanns, Gavin P Dunn
Journal: Journal for ImmunoTherapy of Cancer (2023)

Adoptive cellular therapies with chimeric antigen receptor T cells have revolutionized the treatment of some malignancies but have shown limited efficacy in solid tumors such as glioblastoma and face a scarcity of safe therapeutic targets. As an alternative, T cell receptor (TCR)-engineered cellular therapy against tumor-specific neoantigens has generated significant excitement, but there exist no preclinical systems to rigorously model this approach in glioblastoma.
Lead aVR Should Not Be Neglected
Authors: Zhenyu Dong, Yanmei Lu, Baopeng Tang
Journal: JAMA Internal Medicine (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Direct-to-Consumer Low-Testosterone Clinics—Where Is the Federation of State Medical Boards?
Authors: Steven Woloshin, Lisa L. Gill
Journal: JAMA Internal Medicine (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Lead aVR Should Not Be Neglected—Reply
Authors: Fabrizio Vallelonga, Francesco A. Diella, Stephen W. Smith
Journal: JAMA Internal Medicine (2023)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
TKI Landscape for Ph+ ALL Expanding
Journal: Cancer Discovery (2023)

Preliminary phase III findings support using ponatinib, a third-generation tyrosine kinase inhibitor, as part of standard care for adults newly diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia. In the PhALLCON trial, ponatinib significantly outperformed imatinib, inducing deeper and more durable responses with no added toxicity.
Correction: Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial
Authors: Qian Jiang, Zongru Li, Yazhen Qin, Weiming Li, Na Xu, Bingcheng Liu, Yanli Zhang, Li Meng, Huanling Zhu, Xin Du, Suning Chen, Yang Liang, Yu Hu, Xiaoli Liu, Yongping Song, Lichuang Men, Zi Chen, Qian Niu, Hengbang Wang, Ming Lu, Dajun Yang, Yifan Zhai, Xiaojun Huang
Journal: Journal of Hematology & Oncology (2023)
Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma
Authors: Srirupa Bhattacharyya, Janet L Oblinger, Roberta L Beauchamp, Zhenzhen Yin, Serkan Erdin, Priya Koundinya, Anna D Ware, Marc Ferrer, Justin T Jordan, Scott R Plotkin, Lei Xu, Long-Sheng Chang, Vijaya Ramesh
Journal: Neuro-Oncology (2023)

Abstract Background Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and meningioma, are resistant to chemotherapy, often recurring despite surgery and/or radiation, and have generally shown cytostatic response to signal transduction pathway inhibitors, highlighting the need for improved cytotoxic therapies. Methods Leveraging data from our previous high-throughput drug screening in NF2 preclinical models, we identified a class of compounds targeting the ubiquitin–proteasome pathway (UPP), and undertook studies using candidate UPP inhibitors, ixazomib/MLN9708, pevonedistat/MLN4924, and TAK-243/MLN7243. Employing human primary and immortalized meningioma (MN) cell lines, CRISPR-modified Schwann cells (SCs), and mouse Nf2−/− SCs, we performed dose response testing, flow cytometry-based Annexin V and cell cycle analyses, and RNA-sequencing to identify potential underlying mechanisms of apoptosis. In vivo efficacy was also assessed in orthotopic NF2-deficient meningioma and schwannoma tumor models. Results Testing of three UPP inhibitors demonstrated potent reduction in cell viability and induction of apoptosis for ixazomib or TAK-243, but not pevonedistat. In vitro analyses revealed that ixazomib or TAK-243 downregulates expression of c-KIT and PDGFRα, as well as the E3 ubiquitin ligase SKP2 while upregulating genes associated with endoplasmic reticulum stress-mediated activation of the unfolded protein response (UPR). In vivo treatment of mouse models revealed delayed tumor growth, suggesting a therapeutic potential. Conclusions This study demonstrates the efficacy of proteasomal pathway inhibitors in meningioma and schwannoma preclinical models and lays the groundwork for use of these drugs as a promising novel treatment strategy for NF2 patients.
Quality of Care and Outcomes Among Patients Hospitalized for Heart Failure in Rural vs Urban US Hospitals
Authors: Jacob B. Pierce, Uchechukwu Ikeaba, Anthony E. Peters, Adam D. DeVore, Karen Chiswell, Larry A. Allen, Nancy M. Albert, Clyde W. Yancy, Gregg C. Fonarow, Stephen J. Greene
Journal: JAMA Cardiology (2023)

Importance Prior studies have suggested patients with heart failure (HF) from rural areas have worse clinical outcomes. Contemporary differences between rural and urban hospitals in quality of care and clinical outcomes for patients hospitalized for HF remain poorly understood. Objective To assess quality of care and clinical outcomes for US patients hospitalized for HF at rural vs urban hospitals. Design, Setting, and Participants This retrospective cohort study analyzed 774 419 patients hospitalized for HF across 569 sites in the Get With The Guidelines–Heart Failure (GWTG-HF) registry between January 1, 2014, and September 30, 2021. Postdischarge outcomes were assessed in a subset of 161 996 patients linked to Medicare claims. Data were analyzed from August 2022 to January 2023. Main Outcomes and Measures GWTG-HF quality measures, in-hospital mortality, length of stay, and 30-day mortality and readmission outcomes. Results This study included 19 832 patients (2.6%) and 754 587 patients (97.4%) hospitalized at 49 rural hospitals (8.6%) and 520 urban hospitals (91.4%), respectively. Of 774 419 included patients, 366 161 (47.3%) were female, and the median (IQR) age was 73 (62-83) years. Compared with patients at urban hospitals, patients at rural hospitals were older (median [IQR] age, 74 [64-84] years vs 73 [61-83] years; standardized difference, 10.63) and more likely to be non-Hispanic White (14 572 [73.5%] vs 498 950 [66.1%]; standardized difference, 34.47). In adjusted models, patients at rural hospitals were less likely to be prescribed cardiac resynchronization therapy (adjusted risk difference [aRD], −13.5%; adjusted odds ratio [aOR], 0.44; 95% CI, 0.22-0.92), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (aRD, −3.7%; aOR, 0.71; 95% CI, 0.53-0.96), and an angiotensin receptor–neprilysin inhibitor (aRD, −5.0%; aOR, 0.68; 95% CI, 0.47-0.98) at discharge. In-hospital mortality was similar between rural and urban hospitals (460 of 19 832 [2.3%] vs 20 529 of 754 587 [2.7%]; aOR, 0.86; 95% CI, 0.70-1.07). Patients at rural hospitals were less likely to have a length of stay of 4 or more days (aOR, 0.75; 95% CI, 0.67-0.85). Among Medicare beneficiaries, there were no significant differences between rural and urban hospitals in 30-day HF readmission (adjusted hazard ratio [aHR], 1.03; 95% CI, 0.90-1.19), all-cause readmission (aHR, 0.97; 95% CI, 0.91-1.04), and all-cause mortality (aHR, 1.05; 95% CI, 0.91-1.21). Conclusions and Relevance In this large contemporary cohort of US patients hospitalized for HF, care at rural hospitals was independently associated with lower use of some guideline-recommended therapies at discharge and shorter length of stay. In-hospital mortality and 30-day postdischarge outcomes were similar at rural and urban hospitals.
Molecular changes underlying decay of sensory responses and enhanced seizure propensity in peritumoral neurons
Authors: Elena Tantillo, Marta Scalera, Elisa De Santis, Nicolò Meneghetti, Chiara Cerri, Michele Menicagli, Alberto Mazzoni, Mario Costa, Chiara Maria Mazzanti, Eleonora Vannini, Matteo Caleo
Journal: Neuro-Oncology (2023)

Abstract Background Glioblastoma growth impacts on the structure and physiology of peritumoral neuronal networks, altering the activity of pyramidal neurons which drives further tumor progression. It is therefore of paramount importance to identify glioma-induced changes in pyramidal neurons, since they represent a key therapeutic target. Methods We longitudinal monitored visual evoked potentials after the orthotopic implant of murine glioma cells into the mouse occipital cortex. With laser microdissection, we analyzed layer II-III pyramidal neurons molecular profile and with local field potentials recordings we evaluated the propensity to seizures in glioma-bearing animals with respect to control mice. Results We determine the time course of neuronal dysfunction of glioma-bearing mice and we identify a symptomatic stage, based on the decay of visual response. At that time point, we microdissect layer II-III pyramidal neurons and evaluate the expression of a panel of genes involved in synaptic transmission and neuronal excitability. Compared to the control group, peritumoral neurons show a decrease in the expression of the SNARE complex gene SNAP25 and the alpha1 subunit of the GABA-A receptor. No significant changes are detected in glutamatergic (ie, AMPA or NMDA receptor subunit) markers. Further reduction of GABA-A signaling by delivery of a benzodiazepine inverse agonist, DMCM (methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate) precipitates seizures in 2 mouse models of tumor-bearing mice. Conclusions These studies reveal novel molecular changes that occur in the principal cells of the tumor-adjacent zone. These modifications may be therapeutically targeted to ameliorate patients’ quality of life.